As discussed in our original proposal methyl groups in proteins are pivotal for NMR structural studies on larger proteins. There is considerable overlap in the chemical shift range of the proton resonances of methyl groups in amino acids making resolution of the methyl protons difficult. In addition, only tenuous assignments of the prochiral methyls in valine and leucine residues can be made without isotopic discrimination. While differential "C-labeling of the prochiral methyls of valine has been useful for assignment purposes, the chemical shift dispersion in the carbon dimension makes it desirable to label both methyls in valine and/or leucine with 13C . Therefore, we our plan was to label all of the methyl groups with 13C , and distinguish the prochiral methyl groups by introducing differential deuterium labels. We have developed the a scheme for the synthesis of the chiral methyl labeling in valine. Differentially deuterated methyl iodides have been produced in gram quantities. The isopropyl side chain of valine is produced stereoselectively using the Oppolzer sultam chiral auxiliary. We are now in the final stages of preparing the labeled valine and will incorporate it into the Trp repressor soon. In addition, significant progress has been made toward a new route to labeled This route will allow differential labeling of the imidazole nitrogens and chiral induction of the a-amino group.